Medicinal Chemistry

Our principal research interests lie in the development of novel therapeutic agents for potential use in the treatment of cancer, HIV-1 and bacterial infections. We also have interests in the development of novel nucleic acid biosensors and new in vitro methods for determining key pharmacological parameters of pharmaceutical drugs (e.g. log P, permeability, etc); the latter is undertaken in collaboration with Dr. Arno Kraft.

1. DNA-Binding Ligands

The ability to selectively modulate gene expression will make a major impact in the treatment of a variety of human diseases. Our approach centres on the development of ligands which will bind to DNA in a sequence-selective manner so as to inhibit transcription. The majority of our research in this area is focused on the design and synthesis of novel DNA analogues in which the original sugar-phosphate backbone has been replaced by a peptide backbone e.g. alpha-PNA, alpha-cycloPNA (Figure 1).

Figure 1. Comparison of the structures of DNA, alpha-PNA and alpha-cycloPNA.

2. Anti-HIV-1 Agents

Despite the success of HAART, AIDS remains one of the most urgent world health problems. The therapeutic situation is challenged by rapid emergence of drug resistant strains and so new anti-HIV drugs are needed. We have identified a novel family of non-nucleoside reverse transcriptase inhibitors exemplified by N2-benzyloxycarbonylguan-9-yl acetic acid derivatives 1 (Figure 2). These derivatives were found to be less sensitive to common drug-resistant mutant strains than known NNRTIs.

3. Nucleic Acid Biosensors

The ability to identify particular nucleic acid sequences, both quickly and precisely, has become of increasing importance in recent years. We have embarked on a project to develop a novel colourimetric biosensor in which peptide nucleic acid (PNA)-functionalised lipids are incorporated into polydiacetylene (PDA) liposomes; the PNA is the detector and PDA the sensor. It is envisaged that when PNA binds to its target gene, PDA will be induced to change colour from blue to red (Figure 3).